Protein S Deficiency Evaluation

Physiologic Role

PS is a vitamin K–dependent plasma glycoprotein that serves as a cofactor of APC. When bound to APC it accelerates protein C–dependent degradation of FVa and FVIIIa. In addition, PS may have a protein C–independent antithrombotic activity by serving as a cofactor for tissue factor pathway inhibitor that inactivates FVIIa. Like other vitamin K–dependent coagulation cofactors, it is synthesized primarily in the liver. Approximately 60%–70% of plasma PS is bound to complement factor 4b (C4b) binding protein (C4BP). The remaining PS is not bound and is thus referred to as the PS free fraction. Previously only the free fraction of PS was considered active in anticoagulation, but it has been recently reported that the C4BP bound fraction also has some anticoagulant activity. The significance of the APC-independent activity of PS and that of the C4b-bound PS fraction is a focus of investigation. Current clinical assays measure only APC-dependent PS activity and use the PS free fraction to estimate the concentration of active PS.

Nonhemostatic Function of Protein S

PS has innate immunity functions due to its interaction with C4BP or directly given its capacity to bind negatively charged phospholipids on the surface of apoptotic cells or activated cells. PS serves as a bridge for phagocytic macrophages and potentiates clearance of apoptotic cells. This pathway is so important that bacteria such as group A streptococci have developed toxins (streptococcal pyrogenic exotoxin B) that inhibit PS-mediated phagocytosis. PS also binds the nascent C5, C6, C7 complement complex and prevents inappropriate complement activation and decreases systemic inflammation.

Epidemiology

PS deficiency is inherited in an autosomal dominant fashion and has highly variable penetrance. It is a moderately strong risk factor for venous thrombosis, with a reported adjusted lifetime relative risk increase of about sevenfold in PS-deficient subjects compared with relatives without the deficiency. The first episode of venous thromboembolism (VTE) in patients with PS deficiency generally occurs between the ages of 10 and 50. Heterozygous PS-deficient patients have ∼50% cumulative risk of having a VTE episode before age 50. A role of PS deficiency in arterial thrombosis is not well established with some, but not all studies reporting a mildly increased risk. PS deficiency is rare in the normal Caucasian population, with recent estimates of 0.03%–0.17%. East Asians have a substantially higher prevalence of PS deficiency, with 1%–2% being reported in Japanese healthy donors. PS deficiency is reported in 1%–13% of Caucasian patients with VTE depending on selection criteria and test modality, and as high as 22%–36% of East Asian VTE patients.

Homozygous or compound heterozygous PS deficiency is very rare and often causes catastrophic thrombosis in newborns (called Purpura Fulminants), as well as disseminated intravascular coagulation. It requires lifelong replacement of PS and anticoagulation therapy.

Test Recommendations

Routine screening testing for PS deficiency is not recommended, due to its low prevalence in the general population, leading to the increased probability of false-positive results. General thrombophilia testing guidelines are provided elsewhere in the text (see Chapter 147 ). In addition, testing is appropriate in family members of a known PS deficiency patient. Testing to rule in diagnosis of congenital deficiency should not be performed when the patient is pregnant or within 3 months postpartum, taking oral contraceptives, or has been taking warfarin within the past 30 days. Testing in the immediate aftermath of a thrombotic event and before initiation of warfarin can be used to rule out, but not to rule in, PS deficiency. Because of the multiple physiologic, pathologic, and iatrogenic conditions having a significant effect on PS free and activity levels in the plasma, a low PS value at a single time point should not be overinterpreted as an indication of congenital PS deficiency. Thus, the diagnosis of PS deficiency requires two decreased functional test values, significantly separated in time. In addition, a finding of decreased PS levels in a first-degree relative is helpful for diagnosis of congenital deficiency. A single normal value of PS free antigen or activity test outside of borderline range is usually sufficient to rule out PS deficiency, and follow-up testing is not usually necessary. Testing to assess a risk of arterial thrombotic events is currently not recommended.

Types of Protein S Deficiency

Congenital PS deficiency is subdivided into three types ( Table 151.1 ). Type I is a quantitative deficiency with resulting low levels of total PS, PS activity, and PS free fraction. It is the most frequent of the subtypes and is a result of over 130 different PROS1 mutations. Type II qualitative deficiency is rare (<5% of all PS-deficient patients) and presents with a disproportionate decrease in APC-dependent PS activity relative to PS free fraction and total antigen. Type III deficiency demonstrates normal total PS with low free PS and activity values. Type III PS is a very heterogeneous entity. A large subset of type III deficiencies does not have a clear link to mutations in PROS1 and may be the result of other genetic or epigenetic factors. Another subset cosegregates with type I deficiency within the affected families. Conversions between a type I and type III PS phenotype have been documented with aging in women and are related to increased PS protein levels as women age. Still, a few mutations in PROS1 have been shown to lead to a pure type III phenotype.